Reversible inhibition can profoundly mislead studies on progressive inhibition of enzymes: the interaction of paraoxon with soluble neuropathy target esterase.
Neuropathy target esterase (NTE) is suggested to be the molecular target for the initiation of the organophosphorus induced delayed polyneuropathy (OPIDP). O,O'-diethyl p-nitrophenyl phosphate (paraoxon) was the non-neurotoxic OP of choice for the standard assay of NTE to block the non-relevant esterases (phenylvalerate hydrolases) because it was supposed not to inhibit the enzymic activity of the target protein while N,N'-diisopropyl phosphorodiamidofluoridate (mipafox) is the neuropathic OP used to inhibit (and so to detect) NTE activity. A soluble form of NTE (S-NTE) had previously been described in peripheral nerve which showed a different inhibitor response from that of the particulate NTE (P-NTE). The use of a sequential type of inhibition protocol revealed the presence of an activity component within S-NTE which was extremely sensitive to different esterase inhibitors. Such a soluble activity component remained hidden under the usual concurrent inhibition procedure with paraoxon and was about one order of magnitude more sensitive than P-NTE to the inhibitors studied in the present article. Our results suggest that paraoxon could produce a strong reversible effect on S-NTE when the concurrent procedure is used so that it interferes with its inhibition by both neuropathy inducers and promoters. As a result S-NTE seems to be much more sensitive, than previously believed, to several esterase inhibitors involved in either the genesis of delayed polyneuropathy and/or axonopathy promotion.
Barril
J
J
Universidad Miguel Hernández, Laboratorio de Neurotoxicología, Alicante, Spain.
Vilanova
E
E
D000818:Animals; D015415:Biomarkers; D002265:Carboxylic Ester Hydrolases / Q000037:antagonists & inhibitors* / Q000187:drug effects / Q000378:metabolism; D002645:Chickens; D004791:Enzyme Inhibitors / Q000378:metabolism*; D010261:Paraoxon / Q000633:toxicity*; D010523:Peripheral Nervous System Diseases / Q000139:chemically induced; D012584:Sciatic Nerve / Q000187:drug effects / Q000201:enzymology*; D012995:Solubility; D013379:Substrate Specificity
D015415:Biomarkers; D004791:Enzyme Inhibitors; D002265:Carboxylic Ester Hydrolases; C021859:neurotoxic esterase; D010261:Paraoxon